tbuckley/cabot-search huggingface dataset:
Corticotropin Stimulation in Adrenal Venous Sampling for Patients With Primary Aldosteronism
Authors: Shumin Yang, Zhipeng Du, Xizi Zhang, Qianna Zhen, Xiaoyu Shu, Jun Yang, Ying Song, Yi Yang, Qifu Li, Jinbo Hu, Mei Mei, Suxin Luo, Kangla Liao, Yao Zhang, Yunfeng He, Yihong He, Ming Xiao, Bin Peng
Journal: JAMA Network Open (2023)

Adrenal venous sampling (AVS) is usually recommended to distinguish between unilateral and bilateral primary aldosteronism (PA) before definitive surgical or medical treatment is offered. Whether a treatment decision based on AVS with or without corticotropin (ACTH) stimulation leads to different biochemical and clinical remission rates in patients with PA remains unclear.To evaluate whether treatment decisions based on AVS with or without ACTH stimulation lead to different biochemical and clinical remission rates in patients with PA.This randomized clinical trial (RCT) was conducted at a tertiary hospital in China from July 8, 2020, to February 20, 2023, among patients with PA aged 18 to 70 years. Patients were followed up for 12 months after the initiation of treatment. An intention-to-diagnose analysis was conducted.Patients were randomly assigned to undergo either ACTH-stimulated or non-ACTH-stimulated AVS.The primary end point was the proportion of patients with complete biochemical remission after 12 months of follow-up. Secondary outcomes included the proportion of patients who achieved complete clinical remission after 12 months of follow-up, dosages of antihypertensive agents, rate of successful bilateral AVS, and adverse events.Of 228 patients with PA, 115 were randomized to the non-ACTH-stimulated group (median age, 50.0 years [IQR, 41.0-57.0 years]; 70 males [60.9%]) and 113 to the ACTH-stimulated group (median age, 50.0 years [IQR, 43.5-56.5 years]; 63 males [55.8%]). A total of 68 patients (59.1%) underwent adrenalectomy in the non-ACTH group and 65 (57.5%) in the ACTH group. There was no significant difference in the proportion of patients with complete biochemical remission who were managed on the basis of AVS with vs without ACTH stimulation (with: 56 of 113 [49.6%]; without: 59 of 115 [51.3%]; P = .79). There also was no significant difference in the proportion of patients who achieved complete clinical remission between the non-ACTH and ACTH groups (26 of 115 [22.6%] and 31 of 113 [27.4%], respectively; P = .40). The intensity of therapy with antihypertensives, successful catheterization of bilateral adrenal veins, and incidence of adverse events did not significantly differ between the non-ACTH and ACTH groups.In this RCT, treatment of PA on the basis of non-ACTH-stimulated or ACTH-stimulated AVS did not lead to significant differences in clinical outcomes for the patients. These results suggest that ACTH stimulation during AVS may not have clinical benefit, at least in the Chinese population.ClinicalTrials.gov Identifier: NCT04461535.
Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial
Authors: Funda Meric-Bernstam, Vicky Makker, Ana Oaknin, Do-Youn Oh, Susana Banerjee, Antonio González-Martín, Kyung Hae Jung, Iwona Ługowska, Luis Manso, Aránzazu Manzano, Bohuslav Melichar, Salvatore Siena, Daniil Stroyakovskiy, Anitra Fielding, Yan Ma, Soham Puvvada, Norah Shire, Jung-Yun Lee
Journal: Journal of Clinical Oncology (2023)

PURPOSE Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)–directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non–small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors. METHODS This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths. CONCLUSION Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.
Systematic characterization of antibody–drug conjugate targets in central nervous system tumors
Authors: Shannon Coy, Jong Suk Lee, Sabrina J Chan, Terri Woo, Jacquelyn Jones, Sanda Alexandrescu, Patrick Y Wen, Peter K Sorger, Keith L Ligon, Sandro Santagata
Journal: Neuro-Oncology (2023)

Abstract Background Antibody–drug conjugates (ADCs) enhance the specificity of cytotoxic drugs by directing them to cells expressing target antigens. Multiple ADCs are FDA-approved for solid and hematologic malignancies, including those expressing HER2, TROP2, and NECTIN4. Recently, an ADC targeting HER2 (Trastuzumab-Deruxtecan) increased survival and reduced growth of brain metastases in treatment-refractory metastatic breast cancer, even in tumors with low HER2 expression. Thus, low-level expression of ADC targets may be sufficient for treatment responsiveness. However, ADC target expression is poorly characterized in many central nervous system (CNS) tumors. Methods We analyzed publicly available RNA-sequencing and proteomic data from the children’s brain tumor network (N = 188 tumors) and gene-expression-omnibus RNA-expression datasets (N = 356) to evaluate expression of 14 potential ADC targets that are FDA-approved or under investigation in solid cancers. We also used immunohistochemistry to measure the levels of HER2, HER3, NECTIN4, TROP2, CLDN6, CLDN18.2, and CD276/B7-H3 protein in glioblastoma, oligodendroglioma, meningioma, ependymoma, pilocytic astrocytoma, medulloblastoma, atypical teratoid/rhabdoid tumor (AT/RT), adamantinomatous craniopharyngioma (ACP), papillary craniopharyngioma (PCP), and primary CNS lymphoma (N = 575). Results Pan-CNS analysis showed subtype-specific expression of ADC target proteins. Most tumors expressed HER3, B7-H3, and NECTIN4. Ependymomas strongly expressed HER2, while meningiomas showed weak-moderate HER2 expression. ACP and PCP strongly expressed B7-H3, with TROP2 expression in whorled ACP epithelium. AT/RT strongly expressed CLDN6. Glioblastoma showed little subtype-specific marker expression, suggesting a need for further target development. Conclusions CNS tumors exhibit subtype-specific expression of ADC targets including several FDA-approved for other indications. Clinical trials of ADCs in CNS tumors may therefore be warranted.
A genetic basis of mitochondrial DNAJA3 in nonalcoholic steatohepatitis-related hepatocellular carcinoma
Authors: Ching-Wen Chang, Yu-Syuan Chen, Chen-Hua Huang, Chao-Hsiung Lin, Wailap Victor Ng, Lichieh Julie Chu, Eric Trépo, Jessica Zucman-Rossi, Kevin Siao, Jacquelyn J. Maher, Men Yee Chiew, Chih-Hung Chou, Hsien-Da Huang, Wan-Huai Teo, I-Shan Lee, Jeng-Fan Lo, Xin Wei Wang
Journal: Hepatology (2023)

Background and Aims: NAFLD is the most common form of liver disease worldwide, but only a subset of individuals with NAFLD may progress to NASH. While NASH is an important etiology of HCC, the underlying mechanisms responsible for the conversion of NAFLD to NASH and then to HCC are poorly understood. We aimed to identify genetic risk genes that drive NASH and NASH-related HCC. Approach and Results: We searched genetic alleles among the 24 most significant alleles associated with body fat distribution from a genome-wide association study of 344,369 individuals and validated the top allele in 3 independent cohorts of American and European patients (N=1380) with NAFLD/NASH/HCC. We identified an rs3747579-TT variant significantly associated with NASH-related HCC and demonstrated that rs3747579 is expression quantitative trait loci of a mitochondrial DnaJ Heat Shock Protein Family (Hsp40) Member A3 ( DNAJA3 ). We also found that rs3747579-TT and a previously identified PNPLA3 as a functional variant of NAFLD to have significant additional interactions with NASH/HCC risk. Patients with HCC with rs3747579-TT had a reduced expression of DNAJA3 and had an unfavorable prognosis. Furthermore, mice with hepatocyte-specific Dnaja3 depletion developed NASH-dependent HCC either spontaneously under a normal diet or enhanced by diethylnitrosamine. Dnaja3 -deficient mice developed NASH/HCC characterized by significant mitochondrial dysfunction, which was accompanied by excessive lipid accumulation and inflammatory responses. The molecular features of NASH/HCC in the Dnaja3 -deficient mice were closely associated with human NASH/HCC. Conclusions: We uncovered a genetic basis of DNAJA3 as a key player of NASH-related HCC.
Disentangling the Association Between Excess Thyroid Hormone and Cognition in Older Adults
Authors: Maria Papaleontiou, Juan P. Brito
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2024 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Frequencies of 4 tumor-infiltrating lymphocytes potently predict survival in glioblastoma, an immune desert
Authors: Rotem Gershon, Antonina Polevikov, Yevgeny Karepov, Anatoly Shenkar, Idan Ben-Horin, Tal Alter Regev, Meytal Dror-Levinsky, Kelly Lipczyc, Lital Gasri-Plotnitsky, Gil Diamant, Nati Shapira, Barak Bensimhon, Aharon Hagai, Tal Shahar, Rachel Grossman, Zvi Ram, Ilan Volovitz
Journal: Neuro-Oncology (2023)

GBM is an aggressive grade 4 primary brain tumor (BT), with a 5%-13% 5-year survival. Most human GBMs manifest as immunologically "cold" tumors or "immune deserts," yet the promoting or suppressive roles of specific lymphocytes within the GBM tumor microenvironment (TME) is of considerable debate.
Child Abuse Prevention in a Pandemic—A Natural Experiment in Social Welfare Policy
Authors: Kristine A. Campbell, Joanne N. Wood, Rachel P. Berger
Journal: JAMA Pediatrics (2023)

Nathan L. Maassel, MD; Elena Graetz, PhD; Eric B. Schneider, PhD; Andrea G. Asnes, MSW, MD; Daniel G. Solomon, MD; John M. Leventhal, MD
Alginate microbeads and hydrogels delivering meropenem and bacteriophages to treat Pseudomonas aeruginosa fracture-related infections
Authors: Baixing Chen, Luis Ponce Benavente, Marco Chittò, Jacek K. Wychowaniec, Virginia Post, Matteo D'Este, Caroline Constant, Stephan Zeiter, Wenli Feng, Mercedes González Moreno, Andrej Trampuz, Jeroen Wagemans, Jolien Onsea, R. Geoff Richards, Rob Lavigne, T. Fintan Moriarty, Willem-Jan Metsemakers
Journal: Journal of Controlled Release (2023)
Incorrect Data
Journal: JAMA (2023)

US Preventive Services Task Force; Michael J. Barry, MD; Wanda K. Nicholson, MD, MPH, MBA; Michael Silverstein, MD, MPH; David Chelmow, MD; Tumaini Rucker Coker, MD, MBA; Esa M. Davis, MD, MPH; Katrina E. Donahue, MD, MPH; Carlos Roberto Jaén, MD, PhD, MS; Marti Kubik, PhD, RN; Li Li, MD, PhD, MPH; Gbenga Ogedegbe, MD, MPH; Goutham Rao, MD; John M. Ruiz, PhD; James J. Stevermer, MD, MSPH; Joel Tsevat, MD, MPH; Sandra Millon Underwood, PhD, RN; John B. Wong, MD
Microtubule-Mediated Regulation of β <sub>2</sub> AR Translation and Function in Failing Hearts
Authors: Zoe Kwan, Binoy Paulose Nadappuram, Manton M. Leung, Sanika Mohagaonkar, Ao Li, Kumuthu S. Amaradasa, Ji Chen, Stephen Rothery, Iyobel Kibreab, Jiarong Fu, Jose L. Sanchez-Alonso, Catherine A. Mansfield, Hariharan Subramanian, Alexander Kondrashov, Peter T. Wright, Pamela Swiatlowska, Viacheslav O. Nikolaev, Beata Wojciak-Stothard, Aleksandar P. Ivanov, Joshua B. Edel, Julia Gorelik
Journal: Circulation Research (2023)

β
Regulatory T cells in skin regeneration and wound healing
Authors: Samuel Knoedler, Leonard Knoedler, Martin Kauke-Navarro, Yuval Rinkevich, Gabriel Hundeshagen, Leila Harhaus, Ulrich Kneser, Bohdan Pomahac, Dennis P. Orgill, Adriana C. Panayi
Journal: Military Medical Research (2023)

Abstract As the body’s integumentary system, the skin is vulnerable to injuries. The subsequent wound healing processes aim to restore dermal and epidermal integrity and functionality. To this end, multiple tissue-resident cells and recruited immune cells cooperate to efficiently repair the injured tissue. Such temporally- and spatially-coordinated interplay necessitates tight regulation to prevent collateral damage such as overshooting immune responses and excessive inflammation. In this context, regulatory T cells (Tregs) hold a key role in balancing immune homeostasis and mediating cutaneous wound healing. A comprehensive understanding of Tregs’ multifaceted field of activity may help decipher wound pathologies and, ultimately, establish new treatment modalities. Herein, we review the role of Tregs in orchestrating the regeneration of skin adnexa and catalyzing healthy wound repair. Further, we discuss how Tregs operate during fibrosis, keloidosis, and scarring.
Prenatal Lead Exposure, Genetic Factors, and Cognitive Developmental Delay
Authors: Zhenxian Jia, Hongling Zhang, Ling Yu, Feng Qiu, Yiqing Lv, Jing Guan, Huiqing Gang, Jingwen Zuo, Tongzhang Zheng, Hongxiu Liu, Wei Xia, Shunqing Xu, Yuanyuan Li
Journal: JAMA Network Open (2023)

Importance Although the effects of lead (Pb) exposure on neurocognition in children have been confirmed, the individual associations of prenatal Pb exposure and its interaction with genetic factors on cognitive developmental delay (CDD) in children remain unclear. Objective To investigate the association of prenatal Pb exposure and its interaction with genetic factors with CDD risk. Design, Setting, and Participants Women in Wuhan, China, who had an expected delivery date between March 2014 and December 2017, were recruited for this prospective cohort study. Children were assessed for cognitive development at approximately 2 years of age (March 2016 to December 2019). Maternal venous blood, cord blood, and venous blood from children were collected in a longitudinal follow-up. Data analysis was performed from March 2022 to February 2023. Exposure Prenatal Pb exposure, and genetic risk for cognitive ability evaluated by polygenic risk score constructed with 58 genetic variations. Main Outcomes and Measures Cognitive developmental delay of children aged approximately 2 years was assessed using the Chinese revision of the Bayley Scale of Infant Development. A series of multivariable logistic regressions was estimated to determine associations between prenatal Pb exposure and CDD among children with various genetic backgrounds, adjusting for confounding variables. Results This analysis included 2361 eligible mother-child pairs (1240 boys [52.5%] and 1121 girls [47.5%]; mean [SD] ages of mothers and children, 28.9 [3.6] years and 24.8 [1.0] months, respectively), with 292 children (12.4%) having CDD. Higher maternal Pb levels were significantly associated with increased risk of CDD (highest vs lowest tertile: odds ratio, 1.55; 95% CI, 1.13-2.13), adjusting for demographic confounders. The association of CDD with maternal Pb levels was more evident among children with higher genetic risk (highest vs lowest tertile: odds ratio, 2.59; 95% CI, 1.48-4.55), adjusting for demographic confounders. Conclusions and Relevance In this cohort study, prenatal Pb exposure was associated with an increased risk of CDD in children, especially in those with a high genetic risk. These findings suggest that prenatal Pb exposure and genetic background may jointly contribute to an increased risk of CDD for children and indicate the possibility for an integrated strategy to assess CDD risk and improve children’s cognitive ability.
Impact of radiological response and pattern of progression in patients with hepatocellular carcinoma treated by atezolizumab- bevacizumab
Authors: Claudia Campani, Ariane Vallot, Haroun Ghannouchi, Manon Allaire, Manon Evain, Philippe Sultanik, Sabrina Sidali, Lorraine Blaise, Dominique Thabut, Pierre Nahon, Olivier Seror, Nathalie Ganne-Carrié, Jean-Charles Nault, Mathilde Wagner, Olivier Sutter
Journal: Hepatology (2023)

Background and Aims: We aim to assess the role of radiological response to atezolizumab-bevacizumab in patients with HCC to predict overall survival. Approach and Results: We retrospectively included patients with HCC treated by atezolizumab-bevacizumab in 2 tertiary centers. A retrospective blinded analysis was performed by 2 radiologists to assess Response Evaluation Criteria in Solid Tumor (RECIST 1.1) and modified RECIST (mRECIST) criteria at 12 weeks. Imaging response and treatment decisions in the multidisciplinary tumor board at 12 weeks were registered. Among 125 patients, 9.6% and 20.8% had a response, 39.2% and 35.2% had stable disease, and 51.2% and 44% had progression, according to RECIST 1.1 and mRECIST, respectively, with a substantial interobserver agreement (k coefficient=0.79). Metastasis was independently associated with a higher risk of progression. Patients classified as responders did not reach median survival, which was 16.2 and 15.9 months for patients classified as stable and 9.1 and 9.0 months for patients classified as progressors, in RECIST 1.1 and mRECIST criteria, respectively. We observed a wide variability in the identification of progression in the multidisciplinary tumor board in clinical practice compared with the blind evaluation by radiologists mainly due to discrepancy in the evaluation of the increase in size of intrahepatic lesions. The appearance of new extrahepatic lesions or vascular invasion lesions was associated with a worse overall survival ( p =0.032). Conclusions: RECIST 1.1 and mRECIST criteria predict overall survival with more responders identified by mRECIST and the appearance of new extrahepatic lesion or vascular invasion was associated with a poor prognosis. A noticeable discrepancy was observed between patients classified as progressors at reviewing and the decision reached during the multidisciplinary tumor board.
Adjuvant chemotherapy for resected biliary tract cancers: A fluorouracil-based scheme beats out a gemcitabine-based scheme for the win
Authors: Ya-Fei Hu, Wen-Jie Ma, Yan-Wen Jin, Fu-Yu Li
Journal: Hepatology (2023)

1Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu 610041, China 2Department of Biliary Disease Research Center, West China Hospital of Sichuan University, Chengdu, China Running head: Adjuvant chemotherapy for resected biliary tract cancers Correspondence Yan-Wen Jin, Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China. Add: No. 37 Guo Xue Xiang, Chengdu, Sichuan, 610041, P.R. China. Email: [email protected] Correspondence Fu-Yu Li, Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China. Add: No. 37 Guo Xue Xiang, Chengdu, Sichuan, 610041, P.R. China. Email: [email protected] Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.hepjournal.com.
Endogenous and Exogenous Thyrotoxicosis and Risk of Incident Cognitive Disorders in Older Adults
Authors: Roy Adams, Esther S. Oh, Sevil Yasar, Constantine G. Lyketsos, Jennifer S. Mammen
Journal: JAMA Internal Medicine (2023)

Thyroid hormone is among the most common prescriptions in the US and up to 20% may be overtreated. Endogenous hyperthyroidism may be a risk factor for dementia, but data are limited for iatrogenic thyrotoxicosis.
Percutaneous Intratumoral Immunoadjuvant Gel Increases the Abscopal Effect of Cryoablation for Checkpoint Inhibitor Resistant Cancer
Authors: Avik Som, Jan‐Georg Rosenboom, Eric Wehrenberg‐Klee, Alana Chandler, Gabrielle Ndakwah, Eric Chen, Jack Suggs, Joshua Morimoto, Jonathan Kim, Abdul Rehman Mustafa, Asier Marcos‐Vidal, Florian J. Fintelmann, Arijit Basu, Robert Langer, Giovanni Traverso, Umar Mahmood
Journal: Advanced Healthcare Materials (2023)

Abstract Percutaneous cryoablation is a common clinical therapy for metastatic and primary cancer. There are rare clinical reports of cryoablation inducing regression of distant metastases, known as the “abscopal” effect. Intratumoral immunoadjuvants may be able to augment the abscopal rate of cryoablation, but existing intratumoral therapies suffer from the need for frequent injections and inability to confirm target delivery, leading to poor clinical trial outcomes. To address these shortcomings, an injectable thermoresponsive gel‐based controlled release formulation is developed for the FDA‐approved Toll‐like‐receptor 7 (TLR7) agonist imiquimod (“Imigel”) that forms a tumor‐resident depot upon injection and contains a contrast agent for visualization under computed tomography (CT). The poly‐lactic‐ co ‐glycolic acid‐polyethylene glycol‐poly‐lactic‐ co ‐glycolic acid (PLGA‐PEG‐PLGA)‐based amphiphilic copolymer gel's underlying micellar nature enables high drug concentration and a logarithmic release profile that is additive with the neo‐antigen release from cryoablation, requiring only a single injection. Rheological testing demonstrated the thermoresponsive increase in viscosity at body temperature and radio‐opacity via microCT. Its ability to significantly augment the abscopal rate of cryoablation is demonstrated in otherwise immunotherapy resistant metastatic tumors in two aggressive colorectal and breast cancer dual tumor models with an all or nothing response, responders generally demonstrating complete regression of bilateral tumors in 90‐day survival studies.
Homelessness and Incidence and Causes of Sudden Death
Authors: Leila Haghighat, Satvik Ramakrishna, James W. Salazar, Jean Feng, Joey Chiang, Ellen Moffatt, Zian H. Tseng
Journal: JAMA Internal Medicine (2023)

Over 580 000 people in the US experience homelessness, with one of the largest concentrations residing in San Francisco, California. Unhoused individuals have a life expectancy of approximately 50 years, yet how sudden death contributes to this early mortality is unknown.